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OSU-03012, a novel celecoxib derivative, induces cell swelling and shortens action potential duration in mouse
Shintaro Yamamoto1, Takuya Iyoda, Satomi Kita
1Department of Pharmacology, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jyonan-ku, Fukuoka, Japan. yamamotos@fukuoka-u.ac.jp
Abstract:
OSU03012, a novel celecoxib derivative, has been shown to inhibit proliferation and induce apoptosis in numerous cancer cell lines. However, not much is known about its influence on cell volume regulation and cardiac function in the mammalian heart. We examined the effects of OSU-03012 on cell volume and action potentials in mouse ventricular cells. Video image analysis showed that cell volume increased on application of OSU-03012 in a dose-dependent manner. The action potential duration (APD) at 50% and 90% repolarization (APD(50) and APD(90) respectively) as well as the resting membrane potential (RMP) were measured in current-clamp experiments. OSU-03012 had little effect on APD(50) and RMP but induced approximately 30% shortening of APD(90). These results for cell volume and AP are similar to those in cells under ischaemia/hypoxia, and we confirmed that the shortening of APD(90) was almost completely recovered by glibenclamide, a potent inhibitor of ATP-sensitive potassium channels.We concluded that OSU-03012 may lead to cell swelling and shortening of AP via reduced ATP production in mouse ventricular cells.
Insights
OSU03012, a celecoxib derivative, causes cell swelling and shortens action potential duration in mouse heart cells. This effect is linked to reduced ATP production and is reversible with glibenclamide.
Area of Science:
- Cardiology
- Molecular Pharmacology
- Cell Physiology
Background:
- OSU03012, a celecoxib derivative, inhibits cancer cell proliferation and induces apoptosis.
- Its effects on mammalian cardiac function and cell volume regulation are largely unknown.
Purpose of the Study:
- To investigate the impact of OSU03012 on cell volume and action potentials in mouse ventricular cells.
- To elucidate the underlying mechanisms of OSU03012's cardiac effects.
Main Methods:
- Video image analysis to assess cell volume changes.
- Current-clamp experiments to measure action potentials (APD50, APD90) and resting membrane potential (RMP).
- Application of glibenclamide to investigate the role of ATP-sensitive potassium channels.
Main Results:
- OSU03012 induced a dose-dependent increase in ventricular cell volume.
- It showed minimal effect on APD50 and RMP but significantly shortened APD90 by approximately 30%.
- Glibenclamide largely reversed the APD90 shortening, suggesting ATP-sensitive potassium channel involvement.
Conclusions:
- OSU03012 may induce cell swelling and action potential shortening in mouse ventricular cells.
- These effects appear to be mediated by reduced ATP production, leading to potassium channel activation.
- The findings suggest potential implications for cardiac function under conditions of energy depletion.
